Genetic association studies have identified polymorphism of LDL receptor-related protein-1 (LRP1) as a risk factor for metabolic diseases including premature atherosclerosis. This is a multi- functional receptor that serves as a cargo transporting endocytic receptor for numerous different ligands as well as a receptor with cell signaling properties in modulating cell functions. Results obtained during the past funding period showed LRP1 inactivation in adipocytes yielded animals that are resistant to diet- induced obesity and diabetes. However, the LRP1-deficient adipocytes are dysfunctional with elevated inflammatory gene expression. Our result also showed that liver-specific inactivation of LRP1 reduces HDL production, lowers plasma HDL-cholesterol levels, and promotes injury-induced steatohepatitis and liver cirrhosis. Taken together, these results indicate that LRP1 inactivation in adipose and liver promotes other metabolic disorders despite its protection against diet induced-obesity and diabetes. The latest data revealed LRP1 inactivation reduces lysosomal enzyme processing in both adipocytes and hepatocytes. The goal of this project is to test the overall hypothesis that LRP1 suppresses diet-induced tissue dysfunctions and inflammation and protects against injury-induced steatohepatitis via modulation of lysosomal enzyme sorting and receptor cell signaling events. Specific Aim 1 will delineate the mechanism by which LRP1 deficiency inhibits adipocyte differentiation and promotes adipose dysfunction and inflammation, testing the hypothesis that constitutive PDGF receptor activation along with defective lysosomal enzyme processing and impaired autophagy due to LRP1 deficiency are responsible for these metabolic abnormalities. Specific Aim 2 will test the hypothesis that adipocyte LRP1 deficiency exacerbates vascular occlusive diseases, including diet-induced atherosclerosis and injury-induced neointimal hyperplasia, despite its protection against diet-induced obesity and diabetes. Specific Aim 3 will test the hypothesis that decreased HDL secretion and augmentation of injury-induced liver steatohepatitis observed with hepatic LRP1 deficiency are due to impaired lysosomal enzyme processing and autophagy and/or the reduced clearance of protease-protease inhibitor complexes. Taken together, these studies will clarify the beneficial versus adverse effects of adipose- and liver- specific LRP1 inactivation such that rational therapeutic recommendations can be made for metabolic and cardiovascular risk management. PUBLIC HEALTH RELEVANCE: Genetic association studies have identified polymorphisms of the LDL receptor related protein-1 (LRP1) as a risk factor for metabolic and cardiovascular diseases. This proposal will delineate the mechanism(s) by which LRP1 activities in adipose and liver modulate metabolic disease risk. The clinical implication of this mechanism-based study is that clarification of the beneficial versus adverse effects of adipose- and liver-LRP1 is necessary before any therapeutic recommendations for metabolic and cardiovascular risk management can be made.